Important Safety Information

Cardiac considerations
Like other thiazolidinediones (TZDs), pioglitazone can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure.^[1] In clinical trials, a small number of patients with a history of previously existing cardiac disease were reported to develop congestive heart failure (CHF) when treated with pioglitazone in combination with insulin. Reports of CHF have been received in postmarketing experience in patients with and without previously known heart disease.^[1] Patients with NYHA Class III and IV cardiac status were not studied in pioglitazone clinical trials; therefore, ACTOS, ACTOplus met, and duetact are not indicated in these patients.^[1] Patients with systolic heart failure (NYHA Class II) naïve to pioglitazone therapy should be initiated at the lowest approved dose. Patients should be monitored for signs and symptoms of CHF exacerbation.^[1]

Hepatic safety
Reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal (ULN) have been received in postmarketing experience with pioglitazone. Very rarely, these reports have involved hepatic failure with or without fatal outcome, although causality has not been established.^[1] Liver enzymes, including serum ALT, should be evaluated in all patients at initiation of therapy with ACTOS, ACTOplus met, or duetact, and periodically thereafter per the clinical judgment of the healthcare professional. If ALT >2.5X ULN at baseline or if the patient exhibits clinical evidence of active liver disease, do not initiate therapy with ACTOS, ACTOplus met, or duetact.^[1-3]

Other considerations
ACTOS, ACTOplus met, and duetact may also be associated with hypoglycemia, edema, anemia, weight gain, and/or ovulation in premenopausal, anovulatory women. Adequate contraception should be recommended for premenopausal women.^[1-3] Macular edema has been reported in some diabetic patients receiving TZD therapy, although a causal relationship is unknown. Persons with diabetes should have routine eye exams, and be instructed to immediately report any visual changes to their healthcare provider.

Well-tolerated therapy
In US placebo-controlled ACTOS monotherapy clinical trials, the most common adverse events (≥5%) were upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravated diabetes mellitus, and pharyngitis.^[1] In clinical trials using pioglitazone in combination with metformin, the most common adverse events (≥5%) were upper respiratory tract infection, diarrhea, nausea, headache, urinary tract infection, sinusitis, dizziness, lower limb edema, and increased weight.^[2] In clinical trials using pioglitazone in combination with a sulfonylurea, the most common adverse events (≥5%) were hypoglycemia, upper respiratory tract infection, weight increase, headache, diarrhea, edema, urinary tract infection, pain in limb, and nausea.^[3]

Indications and usage
ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. ACTOS is approved for use as monotherapy and in combination with sulfonylureas, metformin, or insulin when diet and exercise plus the single agent do not result in adequate glycemic control.^[1] ACTOplus met is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and metformin, or whose diabetes is not adequately controlled with metformin alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.^[2] Duetact is indicated with diet and exercise as a once-daily combination therapy to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.^[3] ACTOS, ACTOplus met, and duetact should not be used in patients with type 1 diabetes. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise.^[1-3] The major metabolic defects in type 2 diabetes are peripheral insulin resistance in muscle and fat, decreased pancreatic insulin secretion, and increased hepatic glucose output. Dyslipidemia in insulin resistance is represented by hypertriglyceridemia, decreased HDL levels, and increased small dense LDL particles.^[4] Renal and gastrointestinal function are also clinical considerations when prescribing an oral agent for type 2 diabetes.^[5]

Please view full Prescribing Information for ACTOS.
Please view full Prescribing Information for ACTOplus met.
Please view full Prescribing Information for duetact.

References
1. Charbonnel B, Schernthaner G, Brunetti P, et al. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Diabetologia. 2005;48:1093-1104. 2. ACTOS package insert, Takeda Pharmaceuticals America, Inc. 3. Data on file, Takeda Pharmaceuticals North America, Inc. 4. American Diabetes Association. Standards of medical care in diabetes–2006. Diabetes Care. 2006;29(suppl 1):S4-S42. 5. Duetact package insert, Takeda Pharmaceuticals America, Inc.